Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells
BackgroundEpithelial ovarian cancer (EOC) remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs) in ascites are correlated with tumor progr...
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Frontiers Media S.A.
2017-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01482/full |
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| author | Nirmala Chandralega Kampan Nirmala Chandralega Kampan Nirmala Chandralega Kampan Mutsa Tatenda Madondo Orla M. McNally Andrew N. Stephens Andrew N. Stephens Andrew N. Stephens Michael A. Quinn Magdalena Plebanski Magdalena Plebanski |
| author_facet | Nirmala Chandralega Kampan Nirmala Chandralega Kampan Nirmala Chandralega Kampan Mutsa Tatenda Madondo Orla M. McNally Andrew N. Stephens Andrew N. Stephens Andrew N. Stephens Michael A. Quinn Magdalena Plebanski Magdalena Plebanski |
| author_sort | Nirmala Chandralega Kampan |
| collection | DOAJ |
| description | BackgroundEpithelial ovarian cancer (EOC) remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs) in ascites are correlated with tumor progression and reduced survival. Malignant ascites harbors high levels of Tregs expressing the tumor necrosis factor receptor 2 (TNFR2), as well as pro-inflammatory factors such as interleukin 6 (IL-6) and tumor necrosis factor (TNF). IL-6 is also associated with poor prognosis. Herein, we study the effect of IL-6 and TNF present in ascites on the modulation of TNFR2 expression on T cells, and specifically Tregs.MethodsAscites and respective peripheral blood sera were collected from 18 patients with advanced EOC and soluble biomarkers, including IL-6, sTNFR2, IL-10, TGF-β, and TNF, were quantified using multiplexed bead-based immunoassay. Peripheral blood mononuclear cells (PBMC) from healthy donors were incubated with cell-free ascites for 48 h (or media as a negative control). In some experiments, IL-6 or TNF within the ascites were neutralized by using monoclonal antibodies. The phenotype of TNFR2+ Tregs and TNFR2− Tregs were characterized post incubation in ascites. In some experiments, cell sorted Tregs were utilized instead of PBMC.ResultsHigh levels of immunosuppressive (sTNFR2, IL-10, and TGF-β) and pro-inflammatory cytokines (IL-6 and TNF) were present in malignant ascites. TNFR2 expression on all T cell subsets was higher in post culture in ascites and highest on CD4+CD25hiFoxP3+ Tregs, resulting in an increased TNFR2+ Treg/effector T cell ratio. Furthermore, TNFR2+ Tregs conditioned in ascites expressed higher levels of the functional immunosuppressive molecules programmed cell death ligand-1, CTLA-4, and GARP. Functionally, TNFR2+ Treg frequency was inversely correlated with interferon-gamma (IFN-γ) production by effector T cells, and was uniquely able to suppress TNFR2+ T effectors. Blockade of IL-6, but not TNF, within ascites decreased TNFR2+ Treg frequency. Results indicating malignant ascites promotes TNFR2 expression, and increased suppressive Treg activity using PBMC were confirmed using purified Treg subsets.ConclusionIL-6 present in malignant ovarian cancer ascites promotes increased TNFR2 expression and frequency of highly suppressive Tregs. |
| first_indexed | 2024-12-14T12:45:46Z |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T12:45:46Z |
| publishDate | 2017-11-01 |
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| spelling | doaj.art-0dd567c94a494a328b2b4eed54f0b86a2022-12-21T23:00:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-11-01810.3389/fimmu.2017.01482302344Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T CellsNirmala Chandralega Kampan0Nirmala Chandralega Kampan1Nirmala Chandralega Kampan2Mutsa Tatenda Madondo3Orla M. McNally4Andrew N. Stephens5Andrew N. Stephens6Andrew N. Stephens7Michael A. Quinn8Magdalena Plebanski9Magdalena Plebanski10Department of Immunology and Pathology, Monash University, Melbourne, VIC, AustraliaOncology Unit, Royal Women’s Hospital, Melbourne, VIC, AustraliaDepartment of Obstetrics and Gynaecology, Pusat Perubatan Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaDepartment of Immunology and Pathology, Monash University, Melbourne, VIC, AustraliaOncology Unit, Royal Women’s Hospital, Melbourne, VIC, AustraliaCentre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, AustraliaDepartment of Molecular and Translational Sciences, Monash University, Clayton, VIC, AustraliaEpworth Research Institute, Epworth Healthcare, Richmond, VIC, AustraliaOncology Unit, Royal Women’s Hospital, Melbourne, VIC, AustraliaDepartment of Immunology and Pathology, Monash University, Melbourne, VIC, AustraliaSchool of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, AustraliaBackgroundEpithelial ovarian cancer (EOC) remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs) in ascites are correlated with tumor progression and reduced survival. Malignant ascites harbors high levels of Tregs expressing the tumor necrosis factor receptor 2 (TNFR2), as well as pro-inflammatory factors such as interleukin 6 (IL-6) and tumor necrosis factor (TNF). IL-6 is also associated with poor prognosis. Herein, we study the effect of IL-6 and TNF present in ascites on the modulation of TNFR2 expression on T cells, and specifically Tregs.MethodsAscites and respective peripheral blood sera were collected from 18 patients with advanced EOC and soluble biomarkers, including IL-6, sTNFR2, IL-10, TGF-β, and TNF, were quantified using multiplexed bead-based immunoassay. Peripheral blood mononuclear cells (PBMC) from healthy donors were incubated with cell-free ascites for 48 h (or media as a negative control). In some experiments, IL-6 or TNF within the ascites were neutralized by using monoclonal antibodies. The phenotype of TNFR2+ Tregs and TNFR2− Tregs were characterized post incubation in ascites. In some experiments, cell sorted Tregs were utilized instead of PBMC.ResultsHigh levels of immunosuppressive (sTNFR2, IL-10, and TGF-β) and pro-inflammatory cytokines (IL-6 and TNF) were present in malignant ascites. TNFR2 expression on all T cell subsets was higher in post culture in ascites and highest on CD4+CD25hiFoxP3+ Tregs, resulting in an increased TNFR2+ Treg/effector T cell ratio. Furthermore, TNFR2+ Tregs conditioned in ascites expressed higher levels of the functional immunosuppressive molecules programmed cell death ligand-1, CTLA-4, and GARP. Functionally, TNFR2+ Treg frequency was inversely correlated with interferon-gamma (IFN-γ) production by effector T cells, and was uniquely able to suppress TNFR2+ T effectors. Blockade of IL-6, but not TNF, within ascites decreased TNFR2+ Treg frequency. Results indicating malignant ascites promotes TNFR2 expression, and increased suppressive Treg activity using PBMC were confirmed using purified Treg subsets.ConclusionIL-6 present in malignant ovarian cancer ascites promotes increased TNFR2 expression and frequency of highly suppressive Tregs.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01482/fullepithelial ovarian cancermalignant ascitesinterleukin 6tumour necrosis factor 2FoxP3regulatory T cells |
| spellingShingle | Nirmala Chandralega Kampan Nirmala Chandralega Kampan Nirmala Chandralega Kampan Mutsa Tatenda Madondo Orla M. McNally Andrew N. Stephens Andrew N. Stephens Andrew N. Stephens Michael A. Quinn Magdalena Plebanski Magdalena Plebanski Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells Frontiers in Immunology epithelial ovarian cancer malignant ascites interleukin 6 tumour necrosis factor 2 FoxP3 regulatory T cells |
| title | Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells |
| title_full | Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells |
| title_fullStr | Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells |
| title_full_unstemmed | Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells |
| title_short | Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells |
| title_sort | interleukin 6 present in inflammatory ascites from advanced epithelial ovarian cancer patients promotes tumor necrosis factor receptor 2 expressing regulatory t cells |
| topic | epithelial ovarian cancer malignant ascites interleukin 6 tumour necrosis factor 2 FoxP3 regulatory T cells |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01482/full |
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